The invention relates to novel compositions and methods for enhancing absorption of zwitterionic drugs from the gastrointestinal tract by incorporating therein a mixture of the absorption enhancer palmitoyl carnitine chloride and the solubilizing agent .beta.-cyclodextrin.
Though the gastrointestinal tract is the preferred route for pharmaceutically active compound delivery, all pharmaceutically active compounds are not well absorbed from this site. In many cases, this may be due to the polar nature or hydrophilic character of these pharmaceutically active compounds. Since these compounds are precluded from rapid absorption, such drugs are subject to long residency time in the gastrointestinal environment where both acidic and enzymatic degradation contribute to their poor bioavailability. It is, therefore, clear that any factor which enhances the rate of absorption will demonstrate improved clinical efficacy. In recent years, considerable effort has been directed toward identifying agents which increase gastrointestinal absorption of poorly absorbed compounds. For example, surface active agents (George, Sutter, Finegold, J. Infect. Dis. 136, 822 (1977), chelating agents (Cassidy, Tidball, J. Cell Biol. 32, 672 (1967), salicylates (Higuchi, et al., U.S. Pat. No. 4,462,991 (1984)), anti-inflammatory agents (Yaginuma, et al., Chem. Pharm. Bull. 29, 1974 (1981) and phenothiazines (Alexander and Fix, U.S. Pat. No. 4,425,337 (1984) have been shown to increase gastrointestinal permeability of a variety of drugs. U.S. Pat. Nos. 4,822,733 and 4,537,772 which issued to Alexander, disclose the fact that palmitoyl salts are able to enhance transport of pharmaceutically active compounds from the intestine and into the blood stream.
Although these methods offer improved transport of the pharmaceutically active compound into the blood stream, additional enhancement is often needed. Surprisingly and unexpectedly, Applicant has found that when .beta.-cyclodextrin is added to a formulation of a pharmaceutically active zwitterionic compound and palmitoyl carnitine chloride, a dramatic increase in absorption of the drug from the intestine occurs.
The present use of a combination of palmitoyl carnitine chlorde and .beta.-cyclodextrin to promote gastrointestinal absorption affords several advantages over the prior art's absorption promoting formulations. This novel combination provides greater enhancement and therefore, lower dosages of the pharmaceutically active compounds need to be delivered to the patient. This difference in efficacy further affords opportunities for reducing the required size of the dosage form and potentially minimizing side effects. Enhanced delivery of the pharmaceutically-active ingredient has the additional advantage that absorption does not occur over prolonged intervals during which potentially damaging or irritating compounds might damage the cells which line the intestine. In other words, there is no tissue damage at concentrations of where this combination has been shown to significantly increase drug absorption. In contrast to this, studies have indicated that surfactant activity, with other agents such as sodium lauryl sulfate, is generally associated with some degree of cellular damage. This lack of tissue damage affords a significant advantage to the use of this combination in promoting gastrointestinal drug absorption.
Accordingly, it is an object of this invention to enhance the bioavailability of poorly absorbed pharmaceutically active zwitterionic compounds administered orally or rectally by co-administering these compounds with palmitoyl carnitine chloride and .beta.-cyclodextrin.
A further object of the invention is to provide a new dosage form utilizing a combination of palmitoyl carnitine chloride, .beta.-cyclodextrin and a pharmaceutically active zwitterionic compound which when administered orally or rectally with a therapeutic agent will provide an increased blood level of said therapeutic agent.
Another object of the invention is to provide a formulation which acts as an absorption promoter of gastrointestinal and rectal drug absorption at concentrations which do not alter the normal morphology of the mucosal cells.
Other objects, features and advantages of the invention will be apparent to those skilled in the art from the detailed description of the invention which follows.
All of the foregoing objects are readily attained by providing a composition and method wherein oral and rectal absorption of poorly absorbed pharmaceutically active zwitterionic compounds is enhanced. The method comprises the steps of preparing a dosage form suitable for oral or rectal delivery, the dosage form comprising an effective amount of the poorly absorbed drug, and an effective amount of palmitoyl carnitine chlorde and cyclodextrin.